CN105367473B - Indoline derivative and application thereof in medicine - Google Patents

Abstract

The invention discloses indoline derivatives and application thereof in medicines, and stereoisomers, tautomers, nitric oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the indoline derivatives. The invention also relates to a pharmaceutical composition containing the compound, and the application of the compound or the pharmaceutical composition thereof in preparing medicines for treating and treating 5-HT ₆Receptor-related diseases, in particular Alzheimer's disease.

Description

Indoline derivative and application thereof in medicine

Technical Field

The invention belongs to the field of medicines, and particularly relates to a compound for treating Alzheimer's disease, a pharmaceutical composition containing the compound and application of the compound. In particular, the compounds of the present invention are useful as 5-HT ₆Indoline derivatives of receptor antagonists.

Background

Various central nervous system disorders such as anxiety, depression, etc., are associated with disorders of the neurotransmitters 5-hydroxytryptamine (5-HT) or serotonin. The neurotransmitter 5-hydroxytryptamine (5-HT) functions as the main regulatory neurotransmitter in the brainIs called 5-HT ₁，5-HT ₂，5-HT ₃，5-HT ₄，5-HT ₅，5-HT ₆And 5-HT ₇Are mediated by a large family of receptors. Based on high levels of 5-HT in the brain ₆Receptor mRNA, 5-HT has been proposed ₆Receptors may play a role in the pathology and treatment of central nervous system disorders. In particular, 5-HT has been determined ₆Selective ligands have potential therapeutic utility in certain CNS (central nervous system) disorders, e.g. Parkinson's disease, Huntington's disease, anxiety, depression, manic depression, psychosis, epilepsy, obsessive-compulsive disorders, migraine, Alzheimer's disease (cognitive memory enhancement), sleep disorders, eating disorders (e.g. anorexia and bulimia), panic attacks, ADHD (attention deficit hyperactivity disorder), attention deficit disorder, drug abuse (e.g. cocaine, ethanol, nicotine and benzodiazepines)

Class) and conditions associated with spinal trauma or head injury (e.g., hydrocephalus). The 5-HT is expected ₆Selective ligands may also be useful in the treatment of certain gastrointestinal disorders such as functional bowel disorders. (see, e.g., Roth, B.L., et al, J.Pharmacol. exp. Ther.,1994,268, 1403-14120; Sibley, D.R., et al, Mol, Pharmacol.,1993,43, 320-327; Sleight, A.J., et al, Neurotranssmision, 1995,11,1-5 and Sleight, A.J., et al, Serotonin ID Research Alert,1997,2(3), 115-118).

It was found that known 5-HT ₆Receptor selective antagonists are capable of significantly increasing glutamate and aspartate levels in the frontal cortex without increasing norepinephrine, dopamine, or 5-HT levels. This selective increase in specific neurochemicals noted during memory and cognition strongly suggests 5-HT ₆Role of ligands in cognition (Dawson, L.A.; Nguyen, H.Q.; Li, P., British Journal of Pharmacology,2000,130(1), 23-26). With known selectivity for 5-HT ₆Receptor antagonists have some positive effects on studies of memory and learning in animals (Rogers, D.C.; Hatcher, P.D.；Hagan，J.J.，Society of Neuroscience，Abstracts，2000，26，680)。5-HT ₆A related potential therapeutic use of ligands is in the treatment of attention deficit disorders in children and adults. Because of 5-HT ₆Receptor antagonists appear to increase the activity of the nigrostriatal dopamine pathway and, because ADHD is associated with abnormalities in the caudate nucleus (Ernst, M; Zametkin, A.J.; Matochik, J.H.; Jons, P.A.; Cohen, R.M., journal of Neuroscience, 1998, 18(5), 5901- ₆Receptor antagonists may be useful in the treatment of attention deficit disorders. 5-HT has also been determined ₆Receptor antagonists are potentially useful compounds for the treatment of obesity. See, e.g., Bentley et al, br.j.pharmac.1999, supplement 126; bentley et al, j.psychopharmacol.1997, supplement a 64: 255; wooley et al, Neuropharmacology 2001, 41: 210-129 and WO 02098878.

Disclosure of Invention

The invention provides a compound with 5-HT ₆The indoline derivatives with receptor antagonistic activity have good clinical application prospect. Compared with the existing similar compounds, the compound of the invention is used for treating 5-HT ₆The receptors have a high affinity and show high selectivity and antagonistic properties towards this receptor, while having better pharmacodynamic, pharmacokinetic and/or toxicological properties, such as a good brain/plasma ratio (brain plasma ratio), a good bioavailability, a good metabolic stability or a reduced inhibition of mitochondrial respiration.

The excellent characteristics of some parameters of the compound of the invention, such as half-life period, clearance rate, selectivity, bioavailability, chemical stability, metabolic stability, membrane permeability, solubility and the like, can promote the reduction of side effects, the expansion of therapeutic index or the improvement of tolerance and the like.

The present invention relates to novel indoline derivatives for the treatment of alzheimer's disease and methods of treating alzheimer's disease. The compounds of the present invention and pharmaceutical compositions comprising said compounds are directed to 5-HT ₆The receptor has better affinity function, and particularly has better treatment effect on the Alzheimer disease.

In one aspect, the invention relates to a compound that is a compound of formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof,

wherein, M, Q, R ²、R ³、R ⁴、R ⁵、R ⁶、R ⁷M and k have the meanings given in the description of the invention.

In one embodiment, m is 0,1, 2 or 3.

In one embodiment, k is 0,1, 2,3, 4 or 5.

In one embodiment, Q is CH or N.

In one embodiment, M is-NR ¹-; and R ¹Have the meaning as described in the present invention.

In one embodiment, R ¹Is H, D, C _1-4Alkyl radical, C _2-4Alkenyl radical, C _3-4Alkynyl, C _1-4Haloalkyl, C _3-6Cycloalkyl or heterocyclyl consisting of 3 to 6 ring atoms.

In one embodiment, each R is ²Independently H, D, F, Cl, Br, I, -CN, -NO ₂、-OH、-NH ₂、-C(＝O)-(C _1-6Alkyl), -C (═ O) NH ₂、C _1-6Alkyl radical, C _1-6Alkoxy radical, C _1-6Haloalkyl or C _1-6A haloalkoxy group.

In one embodiment, R ³、R ⁴、R ⁵And R ⁶Each independently is H, D, Cl, Br, I, -CN, -OH, -NH ₂、C _1-6Alkyl radical, C _2-6Alkenyl radical, C _2-6Alkynyl, carboxy-substituted C _1-6Alkyl radical, C _1-6Haloalkyl, C _1-6Haloalkoxy, -C (═ O) CH ₃or-C (═ O) NH ₂。

In one embodiment, each R is ⁷Independently H, D, F, Cl, Br, I, -CN、-NO ₂、-OH、-NH ₂、-C(＝O)-(C _1-6Alkyl), -C (═ O) NH ₂、C _1-6Alkyl radical, C _1-6Alkoxy radical, C _1-6Haloalkyl, C _1-6Haloalkoxy, hydroxy-substituted C _1-6Alkyl or carboxyl substituted C _1-6Alkyl radicals, or R on two adjacent ring carbon atoms ⁷And together with the ring carbon atoms to which they are respectively attached form a substituted or unsubstituted benzene ring or an aromatic heterocyclic ring of 5 to 6 ring atoms.

In one embodiment, R ¹H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl or cyclopentyl.

In one embodiment, each R is ²Independently H, D, F, Cl, Br, I, -CN, -OH, -NH ₂、-C(＝O)CH ₃、-C(＝O)NH ₂Methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, tert-butyloxy, -CHF ₂、-CF ₃、-CH ₂CF ₃、-OCF ₃or-OCH ₂CF ₃。

In one embodiment, R ³、R ⁴、R ⁵And R ⁶Each independently is H, D, Cl, Br, I, -CN, -OH, -NH ₂Methyl, ethyl, n-propyl, isopropyl, tert-butyl, -CHF ₂、-CF ₃、-CH ₂CF ₃、-OCF ₃、-OCH ₂CF ₃、-C(＝O)CH ₃or-C (═ O) NH ₂。

In one embodiment, each R is ⁷Independently H, D, F, Cl, Br, I, -CN, -NO ₂、-OH、-NH ₂、-C(＝O)-(C _1-4Alkyl), -C (═ O) NH ₂、C _1-4Alkyl radical, C _1-4Alkoxy radical, C _1-4Haloalkyl, C _1-4Haloalkoxy, hydroxy-substituted C _1-4Alkyl or carboxyl substituted C _1-4Alkyl radicals, or R on two adjacent ring carbon atoms ⁷Together with the ring carbon atoms to which they are respectively attached to form a substituent orAn unsubstituted benzene ring.

In one embodiment, each R is ⁷Independently H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, tert-butyloxy, -CHF ₂、-CF ₃or-CH ₂CF ₃Or R on two adjacent ring carbon atoms ⁷And together with the ring carbon atoms to which they are respectively attached form an unsubstituted benzene ring.

In one embodiment, the compound of the present invention is a compound having one of the following structures or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound having one of the following structures:

in another aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention.

In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or any combination thereof.

In another embodiment, the pharmaceutical composition of the invention further comprises an additional therapeutic agent, wherein the additional therapeutic agent is a drug for treating alzheimer's disease, a drug for treating a neurological disorder, or a combination thereof.

In yet another embodiment, the additional therapeutic agent described herein is donepezil (donepezil), nalmefene (nalmefene), risperidone (risperidone), vitamin E (vitamine E), SAM-760, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, PRX-8066, RVT-101, naluzaton, idalopidine, tacrine (tacrine), rivastigmine (rivastigmine), galantamine (galantamine), memantine (memantine), Mirtazapine (Mirtazapine), venlafaxine (venlafaxine), despramine (desipramine), nortriptyline (nortriptyline), zolpidem (zolpidem), zopiclone (zocaline), nicergoline (piperacillin), theophylline (theophylline), theobromine (theophylline), theophylline (theophylline), or a theophylline (theophylline), or any combination thereof.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition of the invention in the manufacture of a medicament for the prevention, treatment or amelioration of 5-HT ₆A receptor associated disease.

In one embodiment, the invention relates to the treatment of 5-HT ₆The receptor associated disease is a CNS disorder.

In another embodiment, the invention relates to the treatment of 5-HT ₆Receptor-related CNS disorders are ADHD, anxiety, stress-related diseases, schizophrenia, obsessive-compulsive disorders, manic depression, neurological disorders, memory disorders, attention deficit disorder, parkinson's disease, amyotrophic lateral sclerosis, alzheimer's disease or huntington's chorea.

In one embodiment, the invention relates to the treatment of 5-HT ₆The receptor-associated disease is a gastrointestinal disorder.

In one embodiment, the invention relates to the treatment of 5-HT ₆The receptor-related disease is obesity.

Another aspect of the invention relates to methods for the preparation, isolation and purification of compounds of formula (I).

Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict.

The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below. All references in this specification are incorporated herein by reference in their entirety.

Detailed description of the invention

Definitions and general terms

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.

It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The following definitions, as used herein, should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be found in the descriptions of "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and JerryMarch, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.

The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to one or to more than one (i.e., to at least one) of the objects. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.

The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects, e.g., also primates (e.g., humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "stereoisomers" refers to compounds having the same chemical structure, but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.

The term "chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.

The term "enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.

The term "racemate" or "racemic mixture" refers to an equimolar mixture of two enantiomers lacking optical activity.

The term "diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-Hilldictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; andEliel, E.and Wilen, S, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc, New York, 1994. Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.

Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.

Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and mixtures of non-corresponding isomers (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.

Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.

The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemases and solutions (Wiley Interscience, New York, 1981); principles of Asymmetric Synthesis (2) ^ndEd.Robert E.Gawley,Jeffrey Aube,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tablesof Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of NotreDame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A PracticalApproach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (lowenergy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valenctautomers) include interconversion by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentan-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The term "optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optional bond" means that the bond may or may not be present, and the description includes single, double, or triple bonds.

The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.

The term "unsaturated" or "unsaturated" means that the moiety contains one or more degrees of unsaturation.

The compounds of the invention may be optionally substituted with one or more substituents, as described herein, such as compounds of the general formula above, or as specifically exemplified, sub-classified and encompassed within the examples. It is understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted". In general, the terms "substituted" or "substituted" mean that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein the substituent may be, but is not limited to, deuterium, hydroxyl, amino, fluorine, chlorine, bromine, iodine, cyano, azido, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo (═ O), carboxyl, haloalkyl, haloalkoxy, hydroxyl-substituted alkyl, hydroxyl-substituted haloalkyl, hydroxyl-substituted alkoxy, hydroxyl-substituted alkyl-C (═ O) -, alkyl-S (═ O) ₂-, hydroxy-substituted alkyl-S (═ O) ₂-, carboxyalkoxy, and the like.

In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C _1-6Alkyl "means in particular independently disclosed methyl, ethyl, C ₃Alkyl radical, C ₄Alkyl radical, C ₅Alkyl and C ₆An alkyl group.

In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.

The term "alkyl" or "alkyl group" as used herein, denotes a saturated, straight or branched chain monovalent hydrocarbon radical containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. In one embodiment, the alkyl group contains 1 to 12 carbon atoms; in another embodiment, the alkyl group contains 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH) ₃) Ethyl group (Et, -CH) ₂CH ₃) N-propyl (n-Pr, -CH) ₂CH ₂CH ₃) Isopropyl group (I)i-Pr、-CH(CH ₃) ₂) N-butyl (n-Bu, -CH) ₂CH ₂CH ₂CH ₃) Isobutyl (i-Bu, -CH) ₂CH(CH ₃) ₂) Sec-butyl (s-Bu, -CH (CH) ₃)CH ₂CH ₃) Tert-butyl (t-Bu, -C (CH) ₃) ₃) And so on.

The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp ²A double bond, wherein the alkenyl group is optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH) ₂) Allyl (-CH) ₂CH＝CH ₂) And so on.

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp triple bond, wherein said alkynyl radical is optionally substituted with one or more substituents as described herein. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH) ₂C.ident.CH), 1-propynyl (-C.ident.C-CH) ₃) And so on.

The term "D" or " ²H "represents a single deuterium atom.

The term "heteroatom" denotes one or more of oxygen (O), sulfur (S), nitrogen (N), phosphorus (P) or silicon (Si), including nitrogen (N), sulfur (S) and phosphorus (P) in any oxidation state; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).

The terms "halogen" and "halo" refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

The term "haloalkyl" denotes an alkyl group substituted with one or more halogen atoms, wherein the alkyl group has the meaning described herein, examples of which include, but are not limited to, difluoromethyl, trifluoromethyl, 2,2, 2-trifluoroethyl, 2,2,3, 3-tetrafluoropropyl, and the like. The haloalkyl is optionally substituted with one or more substituents described herein.

The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group is optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH) ₃) Ethoxy (EtO, -OCH) ₂CH ₃) 1-propoxy (n-PrO, n-propoxy, -OCH) ₂CH ₂CH ₃) 2-propoxy (i-PrO, i-propoxy, -OCH (CH) ₃) ₂) 1-butoxy (n-BuO, n-butoxy, -OCH) ₂CH ₂CH ₂CH ₃) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH) ₂CH(CH ₃) ₂) 2-butoxy (s-BuO, s-butoxy, -OCH (CH) ₃)CH ₂CH ₃) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) ₃) ₃) And so on.

The term "haloalkoxy" denotes an alkoxy group substituted with one or more halogen atoms, wherein the alkoxy group has the meaning described herein, examples of which include, but are not limited to, trifluoromethoxy, 2,2, 2-trifluoroethoxy, 2,2,3, 3-tetrafluoropropoxy, and the like. The haloalkoxy group is optionally substituted with one or more substituents as described herein.

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 ring carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl group is optionally substituted with one or more substituents described herein.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 ring atoms in which one or more of the atoms in the ring is independently selected from nitrogen, sulfur, and oxygen atoms, and the ring may be fully saturated or contain one or more degrees of unsaturation, but not one aromatic ring. The heterocyclic group may be a carbon-based or heteroatom group. In the ring-CH ₂-the group is optionally replaced by-C (═ O) -, the sulphur atom in the ring is optionally oxidized to S-oxide and the nitrogen atom in the ring is optionally oxidized to N-oxide. Examples of heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl (oxetan-2-yl, oxetan-3-yl), thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaoxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepinyl, oxacycloheptanyl, oxazepanyl, oxazepinyl, pyrazolinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiopyranyl, piperidinyl, thiomorpholinyl, piperazinyl, dioxanyl, dith Radical, diaza Radical, S-N-aza

Aryl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl, and the like. In heterocyclic radicals of-CH ₂Examples of-groups substituted with-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl, pyrimidinedione, and the like. Examples of sulfur atoms in heterocyclic groups that are oxidized include, but are not limited to, sulfolane, thioMorpholinyl 1, 1-dioxide, and the like. The heterocyclyl group is optionally substituted with one or more substituents described herein.

The term "aryl" denotes monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, at least one of which is aromatic. The aryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the aryl group. The term "aryl" may be used interchangeably with the term "aromatic ring". Examples of the aryl group may include phenyl, naphthyl, and anthracene. The aryl group is optionally substituted with one or more substituents described herein.

The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring is aromatic and at least one ring contains one or more heteroatoms. The heteroaryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the heteroaryl group. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring", "aromatic heterocycle" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein.

Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), and the like, 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl; the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridyl, and the like.

As described herein, the ring system formed by the ring wherein the substituent R is bonded to the center (as shown in formula f) represents any possible substitution or any reasonable substitution of the substituent R on the ring (as in ring A in formula f). For example, formula f represents that any possible substituted position on the A ring may be substituted by a substituent R, such as formula f ¹-f ⁴Shown in the figure:

the term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C) _1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: higuchi et al, Pro-drugs as Novel Delivery Systems, vol.14, a.c.s.symposium Series; roche et al, ed., Bioreversible Cariers in drug design, American Pharmaceutical Association and Pergamon Press, 1987; rautio et al, primers, Design and Clinical Applications, Nature Reviews Drug Discovery,2008,7,255-l, precursors of phospholipids and Phosphates, J.Med.chem.,2008,51, 2328-.

The term "metabolite" as used herein refers to a product obtained by the metabolism of a particular compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: s.m.berge et al, j.pharmaceutical Sciences, 66: 1-19,1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates,palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N ⁺(C _1-4Alkyl radical) ₄A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C _1-8Sulfonates and aromatic sulfonates.

"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.

When the solvent is water, the term "hydrate" may be used. In one embodiment, a molecule of a compound of the present invention may be associated with a molecule of water, such as a monohydrate; in another embodiment, one molecule of the compound of the present invention may be associated with more than one molecule of water, such as a dihydrate, and in yet another embodiment, one molecule of the compound of the present invention may be associated with less than one molecule of water, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the compound in its non-hydrated form.

The term "protecting group" or "PG" refers to a substituent that, when reacted with other functional groups, is generally used to block or protect a particular functionality. For example, "protecting group for amino group" means that a substituent is attached to an amino group to block or protect the functionality of the amino group in a compound, as appropriateThe amino protecting group of (1) includes acetyl, trifluoroacetyl, t-butyloxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethyloxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to the functionality of a substituent of a hydroxy group to block or protect the hydroxy group, and suitable protecting groups include trialkylsilyl, acetyl, benzoyl and benzyl. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH ₂CH ₂SO ₂Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene et al, Protective Groups in organic Synthesis, John Wiley&Sons,New York,1991and Kocienski et al.,Protecting Groups,Thieme,Stuttgart,2005。

The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.

The term "prevent" or "prevention" refers to a reduction in the risk of acquiring a disease or disorder (i.e., arresting the development of at least one clinical symptom of a disease in a subject that may be facing or predisposed to facing such a disease, but who has not yet experienced or exhibited symptoms of the disease).

The term "ADHD" is an abbreviation for Attention-deficiency disorder, a mental disorder that is very common in childhood. This disease is called "hyperactive Disorder" (Hyperkinetic Disorder) according to the world health organization's handbook of Classification of Universal diseases, tenth edition (ICD-10, WHO, 1992), with classification number F90, commonly also known as "hyperactive children".

The term "schizophrenia" refers to schizophrenia, schizophreniform disorder, schizoaffective disorder and psychotic disorder, wherein the term "psychosis" refers to delusions, manifest hallucinations, disorganized speech or disorganized or catatonic behavior. See, Diagnostic and Statistical Manual of Mental Disporder, fourth edition, American Psychiatric Association, Washington, D.C.

Pharmaceutically acceptable acid addition salts may be formed by the action of a compound of the invention with an inorganic or organic acid, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheyl salt, citrate, ethanedisulfonate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/biphosphate/dihydrogen phosphate, dihydrogenphosphate, dihydrogen, Polysilonolactates, propionates, stearates, succinates, sulfosalicylates, tartrates, tosylates and trifluoroacetates.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts may be formed from the compounds of the present invention by reaction with an inorganic or organic base.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of groups I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Some organic amines include, for example, isopropylamine, benzathine (benzathine), choline salts (cholinate), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine, and tromethamine.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, Mack Publishing Company, Easton, Pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, Selection and application (Handbook of pharmaceutical salts: Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany,2002) may find some additional lists of suitable salts.

In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents containing them (e.g., ethanol, DMSO, etc.), for their crystallization. The compounds disclosed herein may form solvates with pharmaceutically acceptable solvents (including water), either inherently or by design; thus, the present invention is intended to include both solvated and unsolvated forms.

Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ²H， ³H， ¹¹C， ¹³C， ¹⁴C， ¹⁵N， ¹⁷O， ¹⁸O， ¹⁸F， ³¹P， ³²P， ³⁵S， ³⁶Cl and ¹²⁵I。

in another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, e.g. wherein a radioisotope, e.g. is present ³H， ¹⁴C and ¹⁸those compounds of F, or in which a non-radioactive isotope is present, e.g. ²H and ¹³C. the isotopically enriched compounds can be used for metabolic studies (use) ¹⁴C) Reaction kinetics study (using, for example ²H or ³H) Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution determination, or may be used in radiotherapy of a patient. ¹⁸F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) can be prepared by conventional techniques known to those skilled in the art or by the procedures and examples described in the present specification using a suitable isotopically labelled reagent in place of the original used unlabelled reagent.

In addition, heavier isotopes are, in particular, deuterium (i.e., ²substitution of H or D) may provide certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or decreased dosage requirements or improved therapeutic index. It is to be understood that deuterium in the present invention is considered as a substituent of the compound of formula (I). The concentration of such heavier isotopes, in particular deuterium, can be defined by isotopic enrichment factorsAnd (4) degree. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic and natural abundance of a given isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g. D ₂O, acetone-d ₆、DMSO-d ₆Those solvates of (a).

Description of the Compounds of the invention

The indoline derivative, the pharmaceutically acceptable salt thereof, the pharmaceutical preparation and the pharmaceutical composition thereof have 5-HT ₆Receptor antagonism, in particular for the treatment of Alzheimer's disease.

The invention also comprises the use of the compounds of the invention and their pharmaceutically acceptable salts for the manufacture of a pharmaceutical product for the treatment of alzheimer's disease, as well as those disorders described herein. The compounds of the invention are also useful for the manufacture of a medicament for alleviating, preventing, controlling or treating 5-HT ₆Receptor mediated disorders, in particular alzheimer's disease. The present invention encompasses pharmaceutical compositions comprising a therapeutically effective amount of a compound represented by formula (I) in combination with at least one pharmaceutically acceptable carrier, adjuvant or diluent.

Unless otherwise indicated, all suitable isotopic variations, stereoisomers, tautomers, nitroxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are within the scope of the present invention.

Unless otherwise indicated, the structural formulae depicted herein include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomers): such as the R, S configuration containing an asymmetric center, the (Z), (E) isomers of the double bond, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers, or geometric isomers (or conformers) thereof are within the scope of the present invention.

Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include isotopically enriched concentrations of one or more different atoms.

The compounds of the present disclosure may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. The present invention contemplates that all stereoisomeric forms of the compounds of formula (I), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers, and mixtures thereof, such as racemic mixtures, are integral to the invention.

In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated as within this invention and are included as disclosed compounds in this invention. When stereochemistry is indicated by a solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of the structure are so well-defined and defined.

Nitroxides of the compounds of the present invention are also included within the scope of the present invention. The nitroxides of the compounds of the present invention may be prepared by oxidation of the corresponding nitrogen-containing basic species using a common oxidizing agent (e.g. hydrogen peroxide) in the presence of an acid such as acetic acid at elevated temperature, or by reaction with a peracid in a suitable solvent, for example peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

In another aspect, the invention relates to intermediates for the preparation of compounds of formula (I).

In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds of formula (I).

In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes materials or compositions which must be compatible chemically or toxicologically, with the other components comprising the formulation, and with the mammal being treated.

Salts of the compounds of the present invention also include, but are not necessarily pharmaceutically acceptable salts of intermediates used in the preparation or purification of the compounds of formula (I) or purified enantiomers of the compounds of formula (I).

If the compounds of the invention are basic, the desired salts may be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids and the like, or using organic acids such as acetic, maleic, succinic, mandelic, fumaric, malonic, pyruvic, oxalic, glycolic and salicylic acids, pyranonic acids such as glucuronic and galacturonic acids, α -hydroxy acids such as citric and tartaric acids, amino acids such as aspartic and glutamic acids, aromatic acids such as benzoic and cinnamic acids, sulfonic acids such as p-toluenesulfonic, ethanesulfonic, and the like.

If the compounds of the invention are acidic, the desired salts can be prepared by suitable methods, e.g., using inorganic or organic bases, such as ammonia (primary, secondary, tertiary), alkali or alkaline earth metal hydroxides, and the like. Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine, piperazine and the like, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

Compounds of the invention and pharmaceutical compositions, formulations and administrations thereof

When useful in therapy, a therapeutically effective amount of a compound of formula (I) and pharmaceutically acceptable salts thereof may be administered as the raw chemical or may be provided as the active ingredient of a pharmaceutical composition. Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of formula (I) or an individual stereoisomer, racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof. In one embodiment of the invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant, or vehicle, and optionally other therapeutic and/or prophylactic ingredients.

Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel h.c.et al, Ansel's Pharmaceutical Dosage Forms and Drug delivery systems (2004) Lippincott, Williams & Wilkins, philidelphia; gennaro a.r.et al, Remington: the Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe R.C., Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.

A method of treatment comprising administering a compound or pharmaceutical composition of the invention, further comprising administering to the patient an additional anti-Alzheimer's disease agent (combination therapy), wherein the additional anti-Alzheimer's disease agent is donepezil, nalmefene, risperidone, vitamin E, SAM-760, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, PRX-8066, RVT-101, naluzaton, idalopidine, tacrine, rivastigmine, nortriptyline, zolpidem, zopiclone, nicergoline, piracetam, selegiline, pentoxifylline, or a combination thereof.

The term "therapeutically effective amount" as used herein refers to the total amount of each active ingredient sufficient to show meaningful patient benefit. When the active ingredient alone is used for separate administration, the term refers only to that ingredient. When used in combination, the term refers to the combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, sequentially or simultaneously. The compound shown as the formula (I) and the pharmaceutically acceptable salt thereof are as described above. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. According to another aspect of the present disclosure there is also provided a process for the preparation of a pharmaceutical formulation, which process comprises admixing a compound of formula (I) or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.

In general, the compounds of the present invention are administered in therapeutically effective amounts by any conventional means of administration for substances that exert similar effects. Suitable dosage ranges are typically from 1 to 500mg per day, preferably from 1 to 100mg per day, most preferably from 1 to 30mg per day, depending on a variety of factors such as the severity of the disease being treated, the age and relative health of the subject being administered, the potency of the compound used, the route and form of administration, the indication for which administration is being made, and the preferences and experience of the relevant medical practitioner. One of ordinary skill in the art of treating such diseases will be able to determine, without undue experimentation and relying on personal knowledge and the disclosure of this application, a therapeutically effective amount of a compound of the present invention for a given disease.

Typically, the compounds of the invention are administered in the form of pharmaceutical formulations including those suitable for oral (including buccal and sublingual), rectal, nasal, topical, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or for administration by inhalation or insufflation. The preferred mode of administration is generally oral, and may be adjusted to the level of pain using a suitable daily dosage regimen.

One or more compounds of the present invention may be presented in pharmaceutical compositions and unit dosage forms together with one or more conventional adjuvants, carriers or diluents. The pharmaceutical compositions and unit dosage forms can contain conventional ingredients in conventional proportions, with or without additional active compounds or ingredients, and the unit dosage forms can contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical compositions may be applied in the form of solids such as tablets or filled capsules, semisolids, powders, sustained release formulations or liquids such as solutions, suspensions, emulsions, elixirs or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of a sterile injectable solution for parenteral use. Thus, formulations containing about 1mg of active ingredient per tablet or, more broadly, from about 0.01 to about 100mg of active ingredient are suitable representative unit dosage forms.

The compounds of the present invention may be formulated in a variety of orally administered dosage forms. Pharmaceutical compositions and dosage forms may comprise one or more compounds of the invention or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutically acceptable carrier may be a solid or a liquid. Formulations in solid form include: powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is typically a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is usually mixed with a carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Powders and tablets preferably contain from about 1% to about 70% of the active compound. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, cocoa butter, and the like. The term "formulation" is intended to include preparations of the active compound that contain the encapsulating material as a carrier to provide a capsule in which the active ingredient, with or without a carrier, is surrounded by the carrier in association therewith. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges are solid forms suitable for oral administration.

Other forms suitable for oral administration include liquid form preparations (including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions) or solid form preparations which are intended to be converted into a liquid form preparation immediately before use. Emulsions may be prepared in solutions such as aqueous propylene glycol or may contain emulsifying agents such as lecithin, sorbitan monooleate or acacia. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickening agents. Aqueous suspensions may be formulated by dispersing the finely divided active ingredient in water with viscous material, for example, natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents. Liquid form preparations include solutions, suspensions, and emulsions, which may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

The compounds of the invention may be formulated for parenteral administration (e.g., by injection, such as bolus injection or continuous infusion) and may be presented in unit dosage form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or non-aqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g. olive oil) and injectable organic esters (e.g. ethyl oleate), and may contain formulatory agents such as preservatives, wetting agents, emulsifying or suspending agents, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic packaging of a sterile solid or by lyophilisation of a solution for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

The compounds of the present invention may be formulated for topical application to the epidermis in the form of an ointment, cream or lotion, or in the form of a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include: lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated for administration in the form of suppositories. The low melting wax, such as a fatty acid glyceride mixture or cocoa butter, can be melted first and the active ingredient dispersed homogeneously, for example by stirring. The molten homogeneous mixture is then poured into a suitably sized mold, allowed to cool and solidify.

The compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

The compounds of the present invention may be formulated for nasal administration. The solutions or suspensions can be applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or nebulizer. The formulations may be in single or multiple dose form. For a dropper or pipette multi-dose form, this may be achieved by the patient administering an appropriate, predetermined volume of solution or suspension. For a nebulizer, this can be achieved, for example, by a metered atomizing spray pump.

The compounds of the invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compounds typically have small particle sizes, for example, on the order of 5 microns or less. The particle size may be obtained by methods well known in the art, for example by micronization. The active ingredient is provided in pressurized packs containing a suitable propellant, such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may also suitably contain a surfactant such as lecithin. The dosage of the medicament may be controlled by a metering valve. Alternatively, the active ingredient may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone. The powder carrier will form a gel in the nasal cavity. The powder compositions may be presented in unit dosage form, for example in gelatin capsules or cartridges or blister packs from which the powder may be administered by means of an inhaler.

If desired, the formulations may be prepared with enteric coatings suitable for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention may be formulated as transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with the treatment regimen is critical. The compounds in transdermal delivery systems are often attached to a skin-adherent solid carrier. The compounds of interest may also be used in combination with a penetration enhancer, such as laurocapram (1-dodecyl azepan-2-one). The sustained release delivery system may be inserted subcutaneously into the subcutaneous layer by surgery or injection. Subcutaneous implants encapsulate compounds in a liquid soluble film, such as silicone rubber, or a biodegradable polymer, such as polylactic acid.

The pharmaceutical preparation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as tablets, capsules, and powders or ampoules in vials. In addition, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in a packaged form.

Other suitable pharmaceutical carriers and their formulations are described in Remington: the Science and Practice of pharmacy 1995 Martin, edited by E.W, Mack Publishing Company, 19 th edition, Easton, Pennsylvania.

Use of the Compounds and pharmaceutical compositions of the invention

The present invention providesThe compound and the pharmaceutical composition can be used for preparing medicines for preventing, treating or reducing Alzheimer's disease and can also be used for preparing medicines for preventing, treating or reducing Alzheimer's disease and 5-HT ₆A pharmaceutical product for a disease associated with a receptor.

The pharmaceutical composition of the invention is characterized by comprising the compound of the invention, in particular the compound shown in the formula (I), and a pharmaceutically acceptable carrier, adjuvant or excipient. The amount of compound in the pharmaceutical composition of the present invention is effective to detectably antagonize 5-HT ₆The receptors are useful for the treatment of CNS disorders, including ADHD, anxiety, stress-related disorders, schizophrenia, obsessive-compulsive disorders, manic depression, neurological disorders, memory disorders, attention deficit disorder, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's chorea, and obesity.

An "effective amount" or "effective dose" of a compound or pharmaceutically acceptable composition of the invention refers to an amount effective to treat or reduce the severity of one or more of the conditions mentioned herein. The compounds and compositions according to the methods of the present invention can be administered in any amount and by any route effective to treat or reduce the severity of the disease. The exact amount necessary will vary depending on the patient, depending on the race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. The compound or composition may be administered in combination with one or more other therapeutic agents, as discussed herein.

In addition to being beneficial for human therapy, the compounds and pharmaceutical compositions of the present invention may also find application in veterinary therapy for pets, animals of the introduced species and mammals in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.

General Synthesis of Compounds of the invention

To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.

In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents than those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Lingkai medicine, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin HaoLiyu Chemicals Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaseiki chemical plant.

The anhydrous tetrahydrofuran is obtained by refluxing and drying the metallic sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, N, N-dimethylacetamide and petroleum ether were used dried over anhydrous sodium sulfate in advance.

The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.

The column chromatography is performed using a silica gel column. SiliconThe glue (300 and 400 meshes) is purchased from Qingdao oceanic chemical plants. Nuclear magnetic resonance spectroscopy with CDC1 ₃、DMSO-d ₆、CD ₃OD or acetone-d ₆As solvent (reported in ppm) TMS (0 ppm) or chloroform (7.25ppm) was used as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet ), m (multiplet, multiplet), br (broad ), dd (doublet of doublets), dt (doublet of triplets ). Coupling constants are expressed in hertz (Hz).

The conditions for determining low resolution Mass Spectrometry (MS) data were: agilent 6120 four-stage rod HPLC-M (column model: Zorbax SB-C18,2.1X 30mm,3.5 micron, 6min, flow rate 0.6 mL/min. mobile phase: 5% -95% (CH with 0.1% formic acid) ₃CN) in (H containing 0.1% formic acid) ₂O) by electrospray ionization (ESI) at 210nm/254nm, with UV detection.

Pure compounds were detected by UV at 210nm/254nm using Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column model: NOVASEP 50/80mm DAC).

The following acronyms are used throughout the invention:

CHCl ₃chloroform

CDC1 ₃Deuterated chloroform

DMSO dimethyl sulfoxide

DMSO-d ₆Deuterated dimethyl sulfoxide

DMF N, N-dimethylformamide

POCl ₃Phosphorus oxychloride

EtOAc/EA ethyl acetate

MgSO ₄Magnesium sulfate

MgCl ₂Magnesium chloride

MeOH,CH ₃OH methanol

CH ₂Cl ₂DCM dichloromethane

mL, mL

M, mol/L mol/liter

PE Petroleum ether (60-90 deg.C)

Na ₂CO ₃Sodium carbonate

NaHCO ₃Sodium bicarbonate

K ₂CO ₃Potassium carbonate

KOH potassium hydroxide

RT Room temperature

Rt Retention time

NaBH ₃CN Cyanoborohydride sodium salt

NaCl sodium chloride

Na ₂SO ₄Sodium sulfate

THF tetrahydrofuran

Et ₃N, TEA Triethylamine

EDTA ethylene diamine tetraacetic acid

PEI polyethyleneimine

Tris-HCl Tris (hydroxymethyl) aminomethane-hydrochloric acid

The following synthetic schemes describe the steps for preparing the compounds disclosed herein. Unless otherwise stated, each R ⁷And k has the definitions as described in the present invention.

Synthesis scheme 1

Formula (A), (B) and 6) The compounds shown can be prepared by general synthetic methods as described in scheme 1, with reference to the following specific procedures: formula (A), (B) and 1) Reacting the compound with bis (2-chloroethyl) amine to obtain a compound of the formula (I) 2) A compound shown in the specification; formula (A), (B) and 2) Reacting the compound with trichloroacetyl chloride under the action of alkali to obtain a compound shown in a formula (A) 3) A compound of the formula (I) followed by 3) The compound reacts under the action of a reducing agent to obtain a compound shown in a formula (I) 4) A compound shown in the specification; formula (A), (B) and 4) The compound is reacted with benzene sulfonyl chloride derivative under the action of alkali ( M) Reaction to obtain the formula ( 5) Amine product of the formula (I) and finally 5) Deprotection of the compound under the action of a base to obtain a compound of the formula (I) 6) The purpose of which is shownThe target product.

The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further illustrated below in connection with the examples.

Examples

Example Synthesis of- ((2-fluorophenyl) sulfonyl) -5- (piperazin-1-yl) indoline

Step 1) Synthesis of 5- (piperazin-1-yl) -1H-indole

5-aminoindole (5.0g,37.8mmol), bis (2-chloroethyl) amine hydrochloride (8.1g,45.4mmol) and potassium carbonate (10.5g,75.6mmol) were added to isopropanol (40mL), and after the reaction solution was reacted at 90 ℃ for 48 hours, dichloromethane (50mL) and methanol (50mL) were added thereto. The reaction mixture was filtered, the filtrate was rotary dried under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give the title compound as a brown solid (4.61g, 60.6%).

MS(ESI,pos.ion)m/z:202.2[M+H] ⁺；

¹H NMR(600MHz,DMSO-d ₆)δ(ppm):10.86(s,1H),7.37(d,J＝9.0Hz,1H),7.24(s,1H),7.01(s,1H),6.85(dd,J＝8.4,1.8Hz,1H),6.30(s,1H),3.02(brs,4H),2.96(brs,4H)。

Step 2) synthesis of 1- (4- (1H-indol-5-yl) piperazine-1-yl) -2,2, 2-trichloro ethanone

5- (piperazin-1-yl) -1H-indole (4.61g,22.86mmol) and triethylamine (9.6mL, 68.6mmol) were added to dichloromethane (50mL) and then a solution of trichloroacetyl chloride (3.1mL, 27.43mmol) in dichloromethane (20mL) was slowly added dropwise thereto, with a low temperature bath at 0 ℃. After the reaction mixture was reacted at room temperature for 4 hours, dichloromethane (50mL) was added to dilute the reaction mixture, and the reaction mixture was washed with a saturated aqueous sodium bicarbonate solution (60 mL). The separated organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give the title compound as a brown solid (4.28g, 54.0%).

MS(ESI,pos.ion)m/z:346.1[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):8.17(s,1H),7.33(d,J＝9.0Hz,1H),7.19(d,J＝1.8Hz,2H),6.97(d,J＝8.4Hz,1H),6.49(s,1H),4.10-3.96(m,4H),3.21(t,J＝4.2Hz,4H)。

Step 3) synthesis of 2,2, 2-trichloro-1- (4- (indolin-5-yl) piperazine-1-yl) ethanone

1- (4- (1H-indol-5-yl) piperazin-1-yl) -2,2, 2-trichloroethanone (7.02g,20.25mmol) was added to acetic acid (15mL) at 25 ℃ and then sodium cyanoborohydride (2.55g,40.5mmol) was added thereto in portions. After the reaction solution reacts for 1 hour, adding a sodium hydroxide solution (mass fraction is 20%) to neutralize the reaction solution until the pH value is 9-10, and then adding ethyl acetate (50mL) to extract the reaction solution. The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was spun dry under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to give the title compound as a brown solid (5.91g, 83.7%).

MS(ESI,pos.ion)m/z:348.0[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):6.84(t,J＝1.2Hz,1H),6.67(dd,J＝8.4,2.4Hz,1H),6.61(d,J＝8.4Hz,1H),4.09-3.84(m,4H),3.55(t,J＝8.4Hz,2H),3.10(t,J＝4.8Hz,4H),3.01(t,J＝8.4Hz,2H)。

Step 4)2,2, 2-trichloro-1- (4- (1- ((2-fluorophenyl) sulfonyl) indolin-5-yl) piperazin-1-yl) ethanone Synthesis of (2)

2,2, 2-trichloro-1- (4- (indolin-5-yl) piperazin-1-yl) ethanone (350mg,1.0mmol) and triethylamine (500. mu.L, 3.61mmol) were added to dichloromethane (10.0mL) at 0 ℃ and then 2-fluorobenzenesulfonyl chloride (274mg,1.41mmol) was slowly added thereto. After the reaction mixture was reacted for ten minutes, the temperature was raised to 25 ℃ to react overnight. Dichloromethane (50mL) was added to the reaction mixture, followed by washing with saturated aqueous sodium chloride (40 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was spun dry under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to give the title compound as a white solid (458mg, 90.4%).

MS(ESI,pos.ion)m/z:506.0[M+H] ⁺；

¹H NMR(400MHz,CDCl ₃)δ(ppm):7.92(td,J＝7.2,1.2Hz,1H),7.55-7.47(m,1H),7.32(d,J＝8.8Hz,1H),7.22(td,J＝8.0,0.8Hz,1H),7.11(td,J＝9.2,0.8Hz,1H),6.73(s,1H),6.70(dd,J＝8.4,2.0Hz,1H),4.14(t,J＝8.4Hz,2H),3.94(brs,4H),3.14(t,J＝4.8Hz,4H),2.99(t,J＝8.4Hz,2H)；

¹³C NMR(100MHz,CDCl ₃)δ(ppm):159.2(d,J＝254.9Hz),147.6,135.2,135.1,133.0,131.5,126.1(d,J＝15.1Hz),124.3(d,J＝3.7Hz),117.3(d,J＝21.9Hz),116.3,115.3,114.3,92.9,50.2(d,J＝3.9Hz),50.0,28.3。

Step 5) Synthesis of 1- ((2-fluorophenyl) sulfonyl) -5- (piperazin-1-yl) indoline

2,2, 2-trichloro-1- (4- (1- ((2-fluorophenyl) sulfonyl) indolin-5-yl) piperazin-1-yl) ethanone (430mg,0.85mmol) was dissolved in tetrahydrofuran (20mL) at 25 ℃ and potassium hydroxide (143mg,2.55mmol, 1mmol/mL aqueous solution was slowly added thereto. After the reaction mixture was stirred and reacted for 24 hours, methylene chloride (60mL) was added, and the separated organic phase was washed with a saturated aqueous solution of sodium chloride (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as a white solid (244mg, 79.4%).

MS(ESI,pos.ion)m/z:362.3[M+H] ⁺；

¹H NMR(400MHz,CDCl ₃)δ(ppm):7.90(td,J＝7.6,1.6Hz,1H),7.53-7.45(m,1H),7.30(d,J＝8.8Hz,1H),7.20(td,J＝7.6,0.8Hz,1H),7.10(td,J＝8.8,0.8Hz,1H),6.70(s,1H),6.68(dd,J＝8.8,3.6Hz,1H),4.13(t,J＝8.4Hz,2H),3.02-3.00(m,4H),2.99(brs,4H),2.95(t,J＝8.4Hz,2H)；

¹³C NMR(100MHz,CDCl ₃)δ(ppm):159.0(d,J＝254.8Hz),149.1,135.0(d,J＝8.4Hz),134.1,132.9,131.5,126.2(d,J＝14.9Hz),124.3(d,J＝3.7Hz),117.2(d,J＝21.9Hz),115.6,115.4,113.6,51.2,50.2(d,J＝4.0Hz),46.1,28.4。

Example Synthesis of 21- ((2-chlorophenyl) sulfonyl) -5- (piperazin-1-yl) indoline

Step 1)2,2, 2-trichloro-1- (4- (1- ((2-chlorophenyl) sulfonyl) indolin-5-yl) piperazin-1-yl) ethanone Synthesis of (2)

The title compound was prepared as described in example 1, step 4 by reacting 2,2, 2-trichloro-1- (4- (indolin-5-yl) piperazin-1-yl) ethanone (350mg,1.0mmol), 2-chlorobenzenesulfonyl chloride (297mg,1.41mmol) and triethylamine (0.5mL,3.61mmol) in dichloromethane (10mL) to give the crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to give the title compound as a white solid (473mg, 90.4%).

MS(ESI,pos.ion)m/z:522.0[M+H] ⁺；

¹H NMR(400MHz,CDCl ₃)δ(ppm):8.14-8.08(m,1H),7.49-7.43(m,2H),7.40-7.34(m,1H),7.18(d,J＝8.8Hz,1H),6.76(d,J＝2.0Hz,1H),6.67(dd,J＝8.8,2.4Hz,1H),4.21(t,J＝8.4Hz,2H),3.94(brs,4H),3.13(t,J＝4.8Hz,4H),3.04(t,J＝8.4Hz,2H)；

¹³C NMR(100MHz,CDCl ₃)δ(ppm):159.3,147.4,136.9,135.7,133.8,132.7,132.4,132.2,132.1,127.0,116.3,114.8,114.6,92.9,50.6,50.1,28.4。

Step 2) Synthesis of 1- ((2-chlorophenyl) sulfonyl) -5- (piperazin-1-yl) indoline

The title compound was prepared as described in example 1, step 5 by reacting 2,2, 2-trichloro-1- (4- (1- ((2-chlorophenyl) sulfonyl) indolin-5-yl) piperazin-1-yl) ethanone (450mg,0.86mmol), potassium hydroxide (145mg,2.58mmol as a 1mmol/mL aqueous solution) in tetrahydrofuran (10mL) to give a crude product which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a pale green solid (266mg, 81.8%).

MS(ESI,pos.ion)m/z:378.1[M+H] ⁺；

¹H NMR(400MHz,CDCl ₃)δ(ppm):8.08(dd,J＝7.6,1.8Hz,1H),7.48-7.40(m,2H),7.34(ddd,J＝8.0,6.0,2.4Hz,1H),7.15(d,J＝8.8Hz,1H),6.73(d,J＝2.0Hz,1H),6.64(dd,J＝8.8,2.4Hz,1H),4.19(t,J＝8.4Hz,2H),3.04-2.95(m,10H)；

¹³C NMR(100MHz,CDCl ₃)δ(ppm):148.8,137.0,134.6,133.6,132.6,132.3,132.1,132.0,126.9,115.6,114.8,113.9,51.3,50.6,46.1,28.4。

Example Synthesis of 31- ((2-bromophenyl) sulfonyl) -5- (piperazin-1-yl) indoline

Step 1)2,2, 2-trichloro-1- (4- (1- ((2-bromophenyl) sulfonyl) indolin-5-yl) piperazin-1-yl) ethanone Synthesis of (2)

The title compound was prepared as described in example 1, step 4 by reacting 2,2, 2-trichloro-1- (4- (indolin-5-yl) piperazin-1-yl) ethanone (350mg,1.0mmol), 2-bromobenzenesulfonyl chloride (359mg,1.41mmol) and triethylamine (0.53mL,3.83mmol) in dichloromethane (10mL) to give a crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to give the title compound as a white solid (529mg, 93.2%).

MS(ESI,pos.ion)m/z:566.0[M+H] ⁺；

¹H NMR(400MHz,CDCl ₃)δ(ppm):8.12(dd,J＝8.0,1.6Hz,1H),7.70(d,J＝7.6Hz,1H),7.43(t,J＝7.2Hz,1H),7.37(td,J＝7.6,1.6Hz,1H),7.17(d,J＝8.4Hz,1H),6.78(s,1H),6.67(dd,J＝8.4,2.0Hz,1H),4.22(t,J＝8.4Hz,2H),3.95(brs,4H),3.14(t,J＝4.8Hz,4H),3.05(t,J＝8.4Hz,2H)；

¹³C NMR(100MHz,CDCl ₃)δ(ppm):159.5,147.4,138.7,135.9,135.8,133.7,132.7,132.1,127.5,120.4,116.3,114.8,114.6,92.9,50.7,50.1,28.4。

Step 2) Synthesis of 1- ((2-bromophenyl) sulfonyl) -5- (piperazin-1-yl) indoline

The title compound was prepared as described in example 1, step 5 by reacting 2,2, 2-trichloro-1- (4- (1- ((2-bromophenyl) sulfonyl) indolin-5-yl) piperazin-1-yl) ethanone (500mg,0.88mmol), potassium hydroxide (148mg,2.64mmol as a 1mmol/mL aqueous solution) in tetrahydrofuran (10mL) to afford a crude product which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to afford the title compound as a pale green solid (290mg, 78.0%).

MS(ESI,pos.ion)m/z:422.1[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):8.09(dd,J＝7.8,1.8Hz,1H),7.69(dd,J＝7.8,1.2Hz,1H),7.40(td,J＝7.8,1.2Hz,1H),7.35(td,J＝7.8,1.2Hz,1H),7.14(d,J＝9.0Hz,1H),6.76(t,J＝1.2Hz,1H),6.66(dd,J＝9.0,3.0Hz,1H),4.22(t,J＝8.4Hz,2H),3.04-3.01(m,6H),3.00-2.98(m,4H)；

¹³C NMR(150MHz,CDCl ₃)δ(ppm):148.9,138.8,135.8,134.8,133.6,132.6,132.1,127.5,120.4,115.6,114.8,113.9,51.4,50.8,46.2,28.4。

Example Synthesis of 41- ((3-fluorophenyl) sulfonyl) -5- (piperazin-1-yl) indoline

Step 1)2,2, 2-trichloro-1- (4- (1- ((3-fluorophenyl) sulfonyl) indolin-5-yl) piperazin-1-yl) ethanone Synthesis of (2)

The title compound was prepared as described in example 1, step 4 by reacting 2,2, 2-trichloro-1- (4- (indolin-5-yl) piperazin-1-yl) ethanone (500mg,1.53mmol), 3-fluorobenzenesulfonyl chloride (0.23mL,1.72mmol) and triethylamine (0.6mL,4.3mmol) in dichloromethane (15mL) to give the crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to give the title compound as a white solid (665mg, 91.5%).

MS(ESI,pos.ion)m/z:506.0[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):7.55(s,1H),7.54(s,1H),7.45(d,J＝7.8Hz,1H),7.42(td,J＝8.4,6.0Hz,1H),7.24(dd,J＝8.4,2.4Hz,1H),6.80(dd,J＝8.4,1.8 Hz,1H),6.70(s,1H),4.00(brs,4H),3.92(t,J＝8.4Hz,2H),3.18(t,J＝4.8Hz,4H),2.82(t,J＝8.4Hz,2H)。

Step 2) Synthesis of 1- ((3-fluorophenyl) sulfonyl) -5- (piperazin-1-yl) indoline

The title compound was prepared as described in example 1, step 5 by reacting 2,2, 2-trichloro-1- (4- (1- ((3-fluorophenyl) sulfonyl) indolin-5-yl) piperazin-1-yl) ethanone (600mg,1.18mmol), potassium hydroxide (196mg,3.5mmol as a 1mmol/mL aqueous solution) in tetrahydrofuran (10mL) to give the crude product which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (332mg, 78.0%).

MS(ESI,pos.ion)m/z:362.2[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):7.51-7.48(m,2H),7.44-7.41(m,1H),7.37(td,J＝8.4,5.4Hz,1H),7.23-7.18(m,1H),6.76(dd,J＝8.4,2.4Hz,1H),6.66-6.65(m,1H),3.88(t,J＝8.4Hz,2H),3.05-3.02(m,4H),3.01-2.97(m,4H),2.76(t,J＝8.4Hz,2H)；

¹³C NMR(150MHz,CDCl ₃)δ(ppm):162.5(d,J＝250.1Hz),149.7,139.2(d,J＝6.5Hz),134.6,133.4,130.9(d,J＝7.7Hz),123.3(d,J＝3.3Hz),120.4(d,J＝21.3Hz),116.4,116.1,114.9(d,J＝24.3Hz),113.6,51.3,50.5,46.3,28.5。

Example Synthesis of 51- ((3-chlorophenyl) sulfonyl) -5- (piperazin-1-yl) indoline

Step 1)2,2, 2-trichloro-1- (4- (1- ((3-chlorophenyl) sulfonyl) indolin-5-yl) piperazin-1-yl) ethanone Synthesis of (2)

The title compound was prepared as described in example 1, step 4 by reacting 2,2, 2-trichloro-1- (4- (indolin-5-yl) piperazin-1-yl) ethanone (500mg,1.43mmol), 3-chlorobenzenesulfonyl chloride (363mg,1.72mmol) and triethylamine (0.5mL,3.56mmol) in dichloromethane (10mL) to afford the crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to afford the title compound as a white solid (561mg, 74.8%).

MS(ESI,pos.ion)m/z:522.0[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):7.74(t,J＝1.8Hz,1H),7.61(d,J＝7.8Hz,1H),7.53(d,J＝8.4Hz,1H),7.52-7.50(m,1H),7.36(t,J＝8.4Hz,1H),6.80(dd,J＝8.4,2.4Hz,1H),6.71(s,1H),3.93(br,4H),3.91(t,J＝8.4Hz,2H),3.17(t,J＝4.8Hz,4H),2.82(t,J＝8.4Hz,2H)。

Step 2) Synthesis of 1- ((3-chlorophenyl) sulfonyl) -5- (piperazin-1-yl) indoline

The title compound was prepared as described in example 1, step 5 by reacting 2,2, 2-trichloro-1- (4- (1- ((3-chlorophenyl) sulfonyl) indolin-5-yl) piperazin-1-yl) ethanone (523mg,1.0mmol), potassium hydroxide (168mg,3.0mmol as a 1mmol/mL aqueous solution) in tetrahydrofuran (10mL) to give a crude product which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (284mg, 75.1%).

MS(ESI,pos.ion)m/z:378.2[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):7.71(t,J＝1.8Hz,1H),7.57-7.55(m,1H),7.49(d,J＝9.0Hz,1H),7.48-7.46(m,1H),7.32(t,J＝8.4Hz,1H),6.77(dd,J＝9.0,2.4Hz,1H),6.67-6.65(m,1H),3.88(t,J＝8.4Hz,2H),3.06-3.02(m,4H),3.01-2.98(m,4H),2.76(t,J＝8.4Hz,2H)；

¹³C NMR(100MHz,CDCl ₃)δ(ppm):149.7,139.0,135.4,134.6,133.5,133.3,130.4,127.6,125.5,116.4,116.2,113.6,51.3,50.5,46.3,28.6。

Example Synthesis of 61- ((3-bromophenyl) sulfonyl) -5- (piperazin-1-yl) indoline

Step 1)2,2, 2-trichloro-1- (4- (1- ((3-bromophenyl) sulfonyl) indolin-5-yl) piperazin-1-yl) ethanone Synthesis of (2)

The title compound was prepared as described in example 1, step 4 by reacting 2,2, 2-trichloro-1- (4- (indolin-5-yl) piperazin-1-yl) ethanone (400mg,1.15mmol), 3-bromobenzenesulfonyl chloride (352mg,1.38mmol) and triethylamine (0.48mL,3.44mmol) in dichloromethane (10mL) to give a crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to give the title compound as a white solid (535mg, 82.2%).

MS(ESI,pos.ion)m/z:566.0[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):7.87(s,1H),7.66-7.61(m,2H),7.51(d,J＝9.0Hz,1H),7.27(t,J＝7.8Hz,1H),6.78(dd,J＝9.0,1.8Hz,1H),6.69(s,1H),3.95(br,4H),3.89(t,J＝8.4Hz,2H),3.17-3.14(m,4H),2.80(t,J＝8.4Hz,2H)。

Step 2) Synthesis of 1- ((3-bromophenyl) sulfonyl) -5- (piperazin-1-yl) indoline

The title compound was prepared as described in example 1, step 5 by reacting 2,2, 2-trichloro-1- (4- (1- ((3-bromophenyl) sulfonyl) indolin-5-yl) piperazin-1-yl) ethanone (500mg,0.88mmol), potassium hydroxide (148mg,2.64mmol as a 1mmol/mL aqueous solution) in tetrahydrofuran (10mL) to give a crude product which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (303mg, 81.5%).

MS(ESI,pos.ion)m/z:422.1[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):7.86(t,J＝1.8Hz,1H),7.64-7.62(m,1H),7.62-7.59(m,1H),7.49(d,J＝8.8Hz,1H),7.26(d,J＝8.4Hz,1H),6.77(dd,J＝8.4,2.4Hz,1H),6.66(d,J＝2.4Hz,1H),3.88(t,J＝8.4Hz,2H),3.05-3.02(m,4H),3.01-2.98(m,4H),2.76(t,J＝8.4Hz,2H)；

¹³C NMR(150MHz,CDCl ₃)δ(ppm):149.8,139.0,136.2,134.5,133.5,130.7,130.5,126.0,123.2,116.5,116.2,113.6,51.3,50.6,46.4,28.6。

Example Synthesis of 71- (benzenesulfonyl) -5- (piperazin-1-yl) indoline

Step 1) synthesis of 2,2, 2-trichloro-1- (4- (1- (benzenesulfonyl) indolin-5-yl) piperazine-1-yl) ethanone

The title compound was prepared as described in example 1, step 4 by reacting 2,2, 2-trichloro-1- (4- (indolin-5-yl) piperazin-1-yl) ethanone (350mg,1.0mmol), benzenesulfonyl chloride (248mg,1.41mmol) and triethylamine (0.48mL,3.44mmol) in dichloromethane (10mL) to give a crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to give the title compound as a white solid (454mg, 92.9%).

MS(ESI,pos.ion)m/z:488.0[M+H] ⁺；

¹H NMR(400MHz,CDCl ₃)δ(ppm):7.77-7.71(m,2H),7.57(d,J＝8.8Hz,1H),7.53(t,J＝7.2Hz,1H),7.42(t,J＝7.0Hz,2H),6.79(dd,J＝8.8,2.4Hz,1H),6.68(d,J＝2.0Hz,1H),3.94(brs,4H),3.89(d,J＝8.4Hz,2H),3.26(t,J＝4.8Hz,4H),2.77(t,J＝8.4Hz,2H)；

¹³C NMR(100MHz,CDCl ₃)δ(ppm):159.4,147.8,137.0,135.9,133.5,133.0,129.0,127.3,116.5,116.3,114.1,92.9,50.2,50.0,28.3。

Step 2) Synthesis of 1- (benzenesulfonyl) -5- (piperazin-1-yl) indoline

The title compound was prepared as described in example 1, step 5 by reacting 2,2, 2-trichloro-1- (4- (1- (phenylsulfonyl) indolin-5-yl) piperazin-1-yl) ethanone (430mg,0.88mmol), potassium hydroxide (148mg,2.64mmol as a 1mmol/mL aqueous solution) in tetrahydrofuran (10mL) to give a crude product which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (252mg, 83.4%).

MS(ESI,pos.ion)m/z:344.1[M+H] ⁺；

¹H NMR(400MHz,CDCl ₃)δ(ppm):7.75-7.69(m,2H),7.53(d,J＝8.8Hz,1H),7.52(t,J＝7.2Hz,1H),7.39(t,J＝8.0Hz,2H),6.77(dd,J＝8.8,2.4Hz,1H),6.65(d,J＝2.0Hz,1H),3.88(t,J＝8.4Hz,2H),3.05-3.03(m,4H),3.01-2.99(m,4H),2.72(t,J＝8.4Hz,2H)；

¹³C NMR(100MHz,CDCl ₃)δ(ppm):149.3,137.1,134.9,133.3,132.9,128.9,127.3,116.4,115.8,113.3,51.1,50.2,46.2,28.4。

Example Synthesis of 85- (piperazin-1-yl) -1-p-toluenesulfonyl indoline

Step 1) synthesis of 2,2, 2-trichloro-1- (4- (1-p-toluenesulfonyl indolin-5-yl) piperazine-1-yl) ethanone

The title compound was prepared as described in example 1, step 4 by reacting 2,2, 2-trichloro-1- (4- (indolin-5-yl) piperazin-1-yl) ethanone (350mg,1.0mmol), p-toluenesulfonyl chloride (268mg,1.41mmol) and triethylamine (0.48mL,3.44mmol) in dichloromethane (10mL) to give a crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to give the title compound as a white solid (476mg, 94.7%).

MS(ESI,pos.ion)m/z:502.1[M+H] ⁺；

¹H NMR(400MHz,CDCl ₃)δ(ppm):7.62(d,J＝8.0Hz,2H),7.56(d,J＝8.4Hz,1H),7.21(d,J＝7.6Hz,2H),6.78(d,J＝7.2Hz,1H),6.68(s,1H),3.93(brs,4H),3.87(d,J＝8.4Hz,2H),3.16(brs,4H),2.78(t,J＝8.4Hz,2H),2.37(s,3H)；

¹³C NMR(100MHz,CDCl ₃)δ(ppm):159.4,147.8,143.9,136.1,134.1,133.4,129.6,127.4,116.5,116.2,114.1,92.9,50.2,50.0,28.3,21.5。

Step 2) Synthesis of 5- (piperazin-1-yl) -1-p-toluenesulfonyl indoline

The title compound was prepared as described in example 1, step 5 by reacting 2,2, 2-trichloro-1- (4- (1-p-toluenesulfonylindolin-5-yl) piperazin-1-yl) ethanone (440mg,0.88mmol), potassium hydroxide (147mg,2.63mmol as a 1mmol/mL aqueous solution) in tetrahydrofuran (10mL) to give the crude product which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a light yellow solid (248mg, 78.8%).

MS(ESI,pos.ion)m/z:358.1[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):7.60(d,J＝7.8Hz,2H),7.53(d,J＝8.4Hz,1H),7.19(d,J＝7.8Hz,2H),6.77(dd,J＝8.4,2.4Hz,1H),6.66(t,J＝1.2Hz,1H),3.86(t,J＝8.4Hz,2H),3.05-3.04(m,4H),3.02-3.00(m,4H),2.74(t,J＝8.4Hz,2H),2.36(s,3H)；

¹³C NMR(150MHz,CDCl ₃)δ(ppm):149.2,143.8,135.0,134.0,133.4,129.6,127.4,116.4,115.9,113.4,51.2,50.2,46.2,28.4,21.5。

Example Synthesis of 91- ((4-methoxyphenyl) sulfonyl) -5- (piperazin-1-yl) indoline

Step 1)2,2, 2-trichloro-1- (4- (1- ((4-methoxyphenyl) sulfonyl) indolin-5-yl) piperazin-1-yl) Synthesis of ethanone

The title compound was prepared as described in example 1, step 4 by reacting 2,2, 2-trichloro-1- (4- (indolin-5-yl) piperazin-1-yl) ethanone (420mg,1.2mmol), p-methoxybenzenesulfonyl chloride (349mg,1.69mmol) and triethylamine (0.48mL,3.44mmol) in dichloromethane (10mL) to give the crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to give the title compound as a white solid (528mg, 84.8%).

MS(ESI,pos.ion)m/z:518.1[M+H] ⁺；

¹H NMR(400MHz,CDCl ₃)δ(ppm):7.67(d,J＝8.8Hz,2H),7.55(d,J＝8.8Hz,1H),6.87(d,J＝8.8Hz,2H),6.78(d,J＝8.4Hz,1H),6.68(s,1H),3.92(brs,4H),3.87(t,J＝8.4Hz,2H),3.81(s,3H),3.16(brs,4H),2.78(t,J＝8.4Hz,2H)；

¹³C NMR(100MHz,CDCl ₃)δ(ppm):163.3,159.4,147.8,136.2,133.5,129.4,128.7,116.5,116.3,114.2,114.1,92.9,55.5,50.2,50.0,28.3。

Step 2)1- ((4-methoxybenzeneSynthesis of yl) sulfonyl) -5-piperazin-1-yl) indoline

The title compound was prepared as described in example 1, step 5 by reacting 2,2, 2-trichloro-1- (4- (1- ((4-methoxyphenyl) sulfonyl) indolin-5-yl) piperazin-1-yl) ethanone (490mg,0.94mmol), potassium hydroxide (159mg,2.83mmol as a 1mmol/mL aqueous solution) in tetrahydrofuran (10mL) to give the crude product which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a pale yellow solid (290mg, 82.6%).

MS(ESI,pos.ion)m/z:374.1[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):7.65-7.61(m,2H),7.51(d,J＝9.0Hz,1H),6.87-6.82(m,2H),6.76(dd,J＝9.0,2.4Hz,1H),6.65(d,J＝2.4Hz,1H),3.84(t,J＝8.4Hz,2H),3.79(s,3H),3.04-3.03(m,4H),3.00-2.99(m,4H),2.72(t,J＝8.4Hz,2H)；

¹³C NMR(150MHz,CDCl ₃)δ(ppm):163.2,149.2,135.1,133.4,129.4,128.6,116.5,115.8,114.1,113.3,55.5,51.2,50.2,46.2,28.4。

Example Synthesis of 101- ((4-fluorophenyl) sulfonyl) -5- (piperazin-1-yl) indoline

Step 1)2,2, 2-trichloro-1- (4- (1- ((4-fluorophenyl) sulfonyl) indolin-5-yl) piperazin-1-yl) ethanone Synthesis of (2)

The title compound was prepared as described in example 1, step 4 by reacting 2,2, 2-trichloro-1- (4- (indolin-5-yl) piperazin-1-yl) ethanone (350mg,1.0mmol), 4-fluorobenzenesulfonyl chloride (240mg,1.2mmol) and triethylamine (0.48mL,3.44mmol) in dichloromethane (10mL) to give the crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to give the title compound as a white solid (514mg, 91.8%).

MS(ESI,pos.ion)m/z:506.0[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):7.75-7.71(m,2H),7.52(d,J＝8.4Hz,1H),7.10-7.05(m,2H),6.77(dd,J＝9.0,2.4Hz,1H),6.68(s,1H),3.97(br,4H),3.87(t,J＝8.4Hz,2H),3.18-3.12(t,J＝4.8Hz,4H),2.77(t,J＝8.4Hz,2H)。

Step 2) Synthesis of 1- ((4-fluorophenyl) sulfonyl) -5- (piperazin-1-yl) indoline

The title compound was prepared as described in example 1, step 5 by reacting 2,2, 2-trichloro-1- (4- (1- ((4-fluorophenyl) sulfonyl) indolin-5-yl) piperazin-1-yl) ethanone (500mg,0.99mmol), potassium hydroxide (168mg,3.0mmol as a 1mmol/mL aqueous solution) in tetrahydrofuran (10mL) to give the crude product which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a pale yellow solid (240mg, 66.2%).

MS(ESI,pos.ion)m/z:362.2[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):7.71(dd,J＝8.4,5.4Hz,2H),7.50(d,J＝9.0Hz,1H),7.06(t,J＝8.4Hz,2H),6.76(dd,J＝9.0,1.8Hz,1H),6.65(s,1H),3.85(t,J＝8.4Hz,2H),3.07-3.02(m,4H),3.02-2.97(m,4H),2.72(t,J＝8.4Hz,2H)；

¹³C NMR(150MHz,CDCl ₃)δ(ppm):165.6(d,J＝253.6Hz),149.7,134.8,133.6,133.3,130.2(d,J＝9.2Hz),116.7,116.4(d,J＝22.2Hz),116.1,113.5,51.3,50.5,46.4,28.6。

Example Synthesis of 111- ((4-chlorophenyl) sulfonyl) -5- (piperazin-1-yl) indoline

Step 1)2,2, 2-trichloro-1- (4- (1- ((4-chlorophenyl) sulfonyl) indolin-5-yl) piperazin-1-yl) ethanone Synthesis of (2)

The title compound was prepared as described in example 1, step 4 by reacting 2,2, 2-trichloro-1- (4- (indolin-5-yl) piperazin-1-yl) ethanone (350mg,1.0mmol), 4-chlorobenzenesulfonyl chloride (262mg,1.2mmol) and triethylamine (0.48mL,3.44mmol) in dichloromethane (10mL) to give the crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to give the title compound as a white solid (494mg, 94.7%).

MS(ESI,pos.ion)m/z:522.0[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):7.65-7.62(m,2H),7.50(d,J＝8.4Hz,1H),7.37-7.34(m,2H),6.76(dd,J＝8.4,2.4Hz,1H),6.67(s,1H),3.98(br,4H),3.86(t,J＝8.4Hz,2H),3.14(t,J＝8.4Hz,4H),2.77(t,J＝8.4Hz,2H)。

Step 2) Synthesis of 1- ((4-chlorophenyl) sulfonyl) -5- (piperazin-1-yl) indoline

The title compound of this step was prepared as described in example 1, step 5 by reacting 2,2, 2-trichloro-1- (4- (1- ((4-chlorophenyl) sulfonyl) indolin-5-yl) piperazin-1-yl) ethanone (490mg,0.94mmol), potassium hydroxide (168mg,3.0mmol as a 1mmol/mL aqueous solution) in tetrahydrofuran (10mL) to afford the crude product which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to afford the title compound as a white solid (252mg, 71.0%).

MS(ESI,pos.ion)m/z:378.2[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):7.63(d,J＝8.4Hz,2H),7.50(d,J＝8.4Hz,1H),7.35(d,J＝8.4Hz,2H),6.76(dd,J＝8.4,2.4Hz,1H),6.65(s,1H),3.86(t,J＝8.4Hz,2H),3.06-3.02(m,4H),3.02-2.97(m,4H),2.74(t,J＝8.4Hz,2H)；

¹³C NMR(150MHz,CDCl ₃)δ(ppm):149.7,139.8,135.6,134.6,133.6,129.4,128.9,116.6,116.0,113.5,51.3,50.5,46.4,28.6。

Example Synthesis of 121- ((4-bromophenyl) sulfonyl) -5- (piperazin-1-yl) indoline

Step 1)2,2, 2-trichloro-1- (4- (1- ((4-bromophenyl) sulfonyl) indolin-5-yl) piperazin-1-yl) ethanone Synthesis of (2)

The title compound was prepared as described in example 1, step 4 by reacting 2,2, 2-trichloro-1- (4- (indolin-5-yl) piperazin-1-yl) ethanone (350mg,1.0mmol), 4-bromobenzenesulfonyl chloride (306mg,1.2mmol) and triethylamine (0.48mL,3.44mmol) in dichloromethane (10mL) to give a crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to give the title compound as a white solid (544mg, 96.2%).

MS(ESI,pos.ion)m/z:566.0[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):7.58-7.56(m,2H),7.54-7.52(m,2H),7.51(d,J＝9.0Hz,1H),6.76(dd,J＝9.0,2.4Hz,1H),6.67(d,J＝2.4Hz,1H),3.98(br,4H),3.86(t,J＝8.4Hz,2H),3.18-3.13(m,4H),2.78(t,J＝8.4Hz,2H)。

Step 2) Synthesis of 1- ((4-bromophenyl) sulfonyl) -5- (piperazin-1-yl) indoline

The title compound was prepared as described in example 1, step 5 by reacting 2,2, 2-trichloro-1- (4- (1- ((4-bromophenyl) sulfonyl) indolin-5-yl) piperazin-1-yl) ethanone (520mg,0.92mmol), potassium hydroxide (168mg,3.0mmol as a 1mmol/mL aqueous solution) in tetrahydrofuran (10mL) to afford a crude product which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to afford the title compound as a white solid (283mg, 73%).

MS(ESI,pos.ion)m/z:422.1[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):7.57-7.54(m,2H),7.53-7.51(m,2H),7.49(d,J＝9.0Hz,1H),6.76(dd,J＝9.0,2.4Hz,1H),6.66-6.64(m,1H),3.85(t,J＝8.4Hz,2H),3.05-3.02(m,4H),3.01-2.98(m,4H),2.74(t,J＝8.4Hz,2H)；

¹³C NMR(150MHz,CDCl ₃)δ(ppm):149.7,136.2,134.6,133.5,132.4,128.9,128.3,116.6,116.0,113.5,51.3,50.5,46.3,28.5。

Biological assay

The compounds of formula (I) were biologically tested using the following experimental methods.

EXAMPLE A radioligand binding assay to evaluate the expression of pairs of compounds of the invention on CHO cellsHuman source 5- ₆Affinity of HT receptors 32 mu g of the prepared expression active human 5-HT ₆CHO cell membrane protein of receptor, 2nM radiolabel [3H]LSD, compounds with different test concentrations, 100 μ M5-HT (5-HT for removing non-specific binding sites) and test buffer were added and mixed well, and the mixture was incubated at 37 ℃ for 120 min; wherein, the components of the test buffer are as follows: 50mM Tris-HCl (pH 7.4), 10mM MgCl ₂0.5mM EDTA, 10. mu.M pargyline and 20mg/L protease inhibitor.

After incubation, the mixture was filtered under vacuum using a glass fiber filter (GF/B, Packard), the filter membrane of which was pre-soaked with 0.3% PEI prior to filtration. After filtration, the filter membrane was washed several times with 50mM Tris-HCl. After the filters are dried, the radioactivity of the filters is counted in a scintillation counter (Topcount, Packard) using scintillation cocktail. Wherein the standard reference compound is 5-HT, and multiple concentrations are tested in each experiment to obtain its competitive inhibition curve, and nonlinear regression analysis is performed on the curve of Hill equation to obtain IC ₅₀The value is calculated by the ChengPrusoff equation to obtain the Ki value.

The compound of the invention is used for treating human 5-HT expressed on CHO cells ₆The results of the receptor affinity assay are shown in table a.

Table a affinity assay results for compounds provided in the examples of the invention

Example No. 2	Ki(nM)	Example No. 2	Ki(nM)
				Example 1	68	Example 5	15
Example 2	55	Example 6	9.3
				Example 4	33	--	--

The test results show that the compound of the invention is in 5-HT ₆The receptor showed higher activity in affinity assay.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an embodiment," "an example," "a specific example" or "some examples" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment, or example is included in at least one embodiment, or example of the invention. In this specification, a schematic representation of the above terms does not necessarily refer to the same embodiment, implementation, or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments, implementations, or examples. Furthermore, the various examples, embodiments, or examples described in this specification, as well as features of various examples, embodiments, or examples, may be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (5)

1. A compound which is a compound having one of the following structures or a pharmaceutically acceptable salt of a compound having one of the following structures:

2. a pharmaceutical composition comprising a compound of claim 1; and

the pharmaceutical composition optionally further comprises a pharmaceutically acceptable carrier, vehicle, or any combination thereof.

3. The pharmaceutical composition of claim 2, further comprising an additional therapeutic agent, wherein the additional therapeutic agent is donepezil, nalmefene, risperidone, vitamins E, SAM-760, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, PRX-8066, RVT-101, naluzaton, idalopidine, tacrine, rivastigmine, galantamine, memantine, mirtazapine, venlafaxine, descumidine, nortriptan, zolpidem, zopiclone, nicergoline, piracetam, selegiline, pentoxifylline, or any combination thereof.

4. Use of a compound according to claim 1 or a pharmaceutical composition according to any one of claims 2 to 3 for the manufacture of a medicament for the prevention, treatment or alleviation of 5-HT ₆A receptor associated disease.

5. The use according to claim 4, wherein the treatment is with 5-HT ₆The receptor-associated disease is a central nervous system disorder, a gastrointestinal disorder, or obesity.